Universities and biotech company smacked down in gene patent case

In a major reversal last week, a U.S. appeals court threw out a broad patent that covered a human gene that is central to many biological processes. The patent had been granted in 2002 to Harvard, MIT, and the Whitehead Institute for Biomedical Research, and until this week, it looked like a gold mine for Ariad Pharmaceuticals, which licensed the patent from the academic institutions.

I’ve made no secret of my opposition to patents on human genes. No one invented our genes, and no one should be given exclusive rights to any gene, or to all the drugs that might depend on a gene – by inhibiting or facilitating its action, for example. The patent in question is a “pathway” patent: it covers any drugs that modulate the gene NF-kB (nuclear factor kappa B), a protein that was discovered in 1986 by scientists at MIT and the Whitehead Institute for Biomedical Research, led by Nobel laureate David Baltimore.

NF-kB is an incredibly well-studied gene that is central to human biology. A search of the PubMed database reveals over 30,000 scientific articles on this gene. NF-kB controls the process by which DNA is copied to make genes (transcription), which means that it is critical to a wide variety of cellular processes. It also plays a key role in our immune system’s response to infections. So in effect, granting a patent on NF-kB is akin to granting a patent on all drugs that affect nearly any human gene. What a great patent! Control NF-kB, and you control the world – well, at least the pharmaceutical world.

The Chronicle of Higher Education reported on the latest decision this week, while most major media outlets missed it. Back in 2006, when Ariad won the original lawsuit, the New York Times and CNN (among others) both reported that a federal court ordered Eli Lilly & Co. to pay $65.2 million in royalties to Ariad Pharmaceuticals. In addition to this large cash award, Lilly was ordered to pay a 2.3% royalty on future sales of Evista, an osteoporosis drug, and Xigris, a drug for septic shock.

Ka-ching! This victory appeared to be a jackpot for Ariad. All it did was license the patent from the academic institutions – it didn’t actually produce any drugs based on the patent. Ariad and the academics filed a lawsuit against Eli Lilly on the day the patent was granted. Make no mistake, this patent was purely about greed.

The original ruling threatened many other companies besides Eli Lilly. For example, Amgen challenged the patent after the 2006 ruling, worried that its rheumatoid arthritis drugs Enbrel(R) and Kineret(R), would also be affected.

The patent itself, which can be found here, is incredibly broad. Its first claim, for example, is for any method “inhibiting expression, in a eukaryotic cell, of a gene whose transcription is regulated by NF-kB.” This language covers hundreds of other genes beyond NF-kB – and this is merely the first of 203 claims in the patent!

No, I am not a shill for Big Pharma, even though a big company is the winner here. (See some of my blogs attacking Big Pharma here and here, for example.) The NF-kB patent is a clear example of why we should not allow patents on human genes, and at the same time it illustrates how greedy university tech transfer offices are all too happy to apply for any patent they can, provided they see a profit in it. The presidents of Harvard, MIT, and the Whitehead Institute should never have filed this claim, and I’m delighted that the courts have done the right thing in striking it down.

Vaccine court ruling: thimerosal does not cause autism

Does thimerosal, a preservative used in some vaccines, cause autism?

Thimerosal is a mercury-containing compound that has been used since the 1930s as a preservative in vaccines. Why was thimerosal introduced into vaccines? Well, early vaccines were administered from multi-dose bottles, in which bacteria could grow. In one particularly disastrous incident in 1928, 12 children in Australia died from staph infections after getting the diptheria vaccine from the same multi-dose bottle. After the introduction of thimerosal, bacterial infections caused by vaccination virtually disappeared.

Fast-forward 70 years, to the modern anti-vaccination movement. Following the late 1990s, a small number of activists, led in more recent years by J.B. Handley (who founded Generation Rescue in 2005) and a few others, decided that the mercury in vaccines causes autism. Robert F. Kennedy Jr. wrote articles promoting his crackpot notion of a large government conspiracy to cover up the harm being caused by thimerosal. The movement took off, especially after former Playboy model Jenny McCarthy became the “face” of Generation Rescue.

Was there every any scientific support for the link between thimerosal and autism? From the late 1990s to the present, scientists have looked closely at the evidence, and every well-done study has pointed to the same conclusion: thimerosal in vaccines has no link to autism. In one very large Danish study, autism rates rose after thimerosal was removed from vaccines. Another study looking at California, Sweden, and Denmark found the same thing. These results directly contradict the claim that thimerosal causes autism.

Despite the lack of evidence, the anti-vaxers have continued to wage their war against vaccines on two fronts. Last month, they lost the final battle in one effort, which claimed that the measles-mumps-rubella (MMR) vaccine causes autism. That battle started with the now-discredited 1998 study published in The Lancet by Andrew Wakefield. After the British General Medical Council ruled that Wakefield acted “dishonestly and irresponsibly”, the Lancet formally retracted the original paper, and a few days later Wakefield was forced to resign from the institute he founded in the U.S. to promote his claims.

Thimerosal was the “second front” in the anti-vax war, and now they’ve lost this one too. Last Friday, a special vaccine court ruled on three cases in which parents were suing on behalf of their autistic children. In each case, the parents claimed that thimerosal had caused their child’s autism. In each case, the Special Master (a judge) ruled definitively against the parents. The result was a slam-dunk win for science.

The three rulings take up over 600 pages, far too much to summarize, so I’ll just excerpt briefly from two of the conclusions. Special Master Denise Vowell, in the Dwyer case, issued a particularly devastating decision, ruling that claims about mercury were completely implausible and that the parents’ notion of “regressive autism” had no basis in science:

Petitioners propose effects from mercury … that do not resemble mercury’s known effects on the brain, either behaviorally or at the cellular level. To prevail, they must show that the exquisitely small amounts of mercury in TCVs [thimerosal-containing vaccines] that reach the brain can produce devastating effects that far larger amounts experienced prenatally or postnatally from other sources do not. … In an effort to render irrelevant the numerous epidemiological studies of ASD [autism spectrum disorder] and TCVs that show no connection between the two, they contend that their children have a form of ASD involving regression that differs from all other forms biologically and behaviorally. World-class experts in the field testified that the distinctions they drew between forms of ASD were artificial, and that they had never heard of the “clearly regressive” form of autism about which petitioners’ epidemiologist testified. Finally, the causal mechanism petitioners proposed would produce, not ASD, but neuronal death, and eventually patient death as well. The witnesses setting forth this improbable sequence of cause and effect were outclassed in every respect by the impressive assembly of true experts in their respective fields who testified on behalf of respondent.

It’s interesting that Vowell found that even if the “exquisitely small” amounts of mercury in vaccines had an effect, they wouldn’t cause autism. It was also somewhat sad to see how a well-known statistician, UCLA professor Sander Greenland, appearing in support of the thimerosal-autism link, embarrassed himself by presenting testimony that “largely represented an opinion based on a set of assumptions,” according to the ruling. Greenland’s arguments relied entirely on the existence of “clearly regressive autism,” but the Special Master pointed out that Greenland “was not qualified to opine on its existence.” Ouch.

And here is an excerpt from the 122-page decision of Special Master George Hastings in the King case:

...the evidence is overwhelmingly contrary to the petitioners’ contentions. The expert witnesses presented by the respondent were far better qualified, far more experienced, and far more persuasive than the petitioners’ experts, concerning the key points. The numerous medical studies concerning the issue of whether thimerosal causes autism, performed by medical scientists worldwide, have come down strongly against the petitioners’ contentions. Considering all of the evidence, I find that the petitioners have failed to demonstrate that thimerosal-containing vaccines can contribute to the causation of autism.”

I’m not optimistic that these clear, decisive rulings will have any effect on the conspiracy theorists in the anti-vax movement. Indeed, over at Age of Autism, they’ve already posted an article titled “Special Masters Protect Vaccine Program and Deny Justice to Vaccine-Injured Children.” The article, which is a combination of denialism and conspiracy mongering, claims that the trials ignored the science in order to defend the government’s vaccine program.

On the contrary, scientists studying autism want nothing more than to understand its cause and eventually to produce effective treatments. A growing body of evidence points to genetic factors behind ASD, but it will take much more work to pin down the complex combinations of genes that cause the various behaviors now called autism spectrum disorder. For example, a recent (2007) study by Sebat et al. found a clear link between ASD and de novo copy number variation (de novo mutations are those that arise for the first time in the children). We need more studies like this one if we’re to figure out this disease.

After the ruling, Alison Singer of the Autism Science Foundation said “It's time to move forward and look for the real causes of autism.” Well said. I hope that some in the anti-vax movement will recognize that if they truly want to find a cure for autism, they will support the science instead of insisting, as they do now, that more effort be poured into research on discredited hypotheses. The thimerosal-autism hypothesis is dead.